Glaucoma is a term used to describe a group of diseases characterized by the loss of retinal ganglion cells and their axons and is one of the leading causes of blindness in the world. In many cases, vision loss due to glaucoma is irreversible. Glaucoma diagnosis is most commonly associated with an increase in intraocular pressure (IOP); however, diagnosis may also be based on the assessment of the optic nerve head (ONH), visual function, and/or the health and thickness of the retinal nerve fiber layer (RNFL). Methods of OCT glaucoma analysis have been based primarily on a scan pattern centered at the optic nerve head (ONH), where the ganglion cell axons (or retinal nerve fiber layer—RNFL) converge to exit the eye. Structural measurements that are clinically relevant to the disease include measurements of the thickness of the RNFL in the peripapillary region as well as measurements of characteristics of the optic nerve head such as ‘cupping’. Both of these methods have been developed commercially (Carl Zeiss Meditec Cirrus version 5.1 software) and are accepted as good structural indicators of disease status. The scan pattern used for both measurements is the Optic Disc Cube, which is 200-by-200 A-scans, covering a 6 mm-by-6 mm lateral area, and 2 mm axial depth.
As measured, the RNFL or ganglion cell axons are perhaps the gold-standard, automated structural measurement for glaucoma management. It is not clear whether it is the axons or the cells themselves that die first in glaucoma. The ganglion cell bodies are distributed throughout the eye, but have the greatest density around the fovea and receive electrical signals from the photoreceptors (the rods and cone cells). These signals are then organized and passed onward through the RNFL via the optic nerve head to the brain's lateral geniculate body for further processing before being sent to the visual cortex. The ganglion cell bodies form the ganglion cell layer (GCL), which, it is hypothesized, might show the earliest signs of glaucomatous damage. (See Leung et al., “Comparison of macular and peripapillary measurements for the detection of glaucoma: an optical coherence tomography study” Ophthalmology 2005 March; 112(3):391-400.)
FIG. 1 shows the various layers at the macula. The anterior boundary of the GCL is the posterior boundary of the RNFL, or the ILM where no RNFL exists. It can be seen that the GCL's posterior boundary is very faint, which may be in part an answer as to why the RNFL is instead measured in current instruments; i.e., it can more easily be seen and measured. In fast, volumetric scans about the macula, the GCL can be seen in only the minority of cases. This, in turn, has led researchers to segment a so-called ganglion cell complex (GCC). That is, they include additional, surrounding layers with the objective of making the GCC a measurable entity. One such segmentation is available commercially from Optovue, where the GCC is defined as the RNFL+GCL+IPL (see U.S. Patent Publication No. 2008/0309881). The segmentation task is still non-trivial, and that is probably why the metric has yet to be proven to be better than the gold standard of peripapillary RNFL thickness with respect to efficacy in detecting disease.
FIG. 2 shows a reason to avoid including the RNFL in the ganglion cell complex. The top row of the figure shows thickness maps or images derived from macular scans of four normal subjects, segmented to identify the thickness of the ganglion cell complex including the RNFL, ganglion cell and inner plexiform layers. The bottom row shows maps from the same scans, segmenting only the GCL and the IPL. The distribution of RNFL varies as a result of an individual's anatomy, and it is possible that this variability exceeds the variation due to glaucoma (see Ozden-Gurses et al., “Distribution of retinal nerve fiber layer thicknesses using Cirrus™HD-OCT Spectral Domain technology” ARVO 2008 Program #A258, Poster #4632). A characterization that does not include the RNFL layer may present a topographically more homogeneous base from which to visualize defects and damage due to the presence of disease, and thereby provide a better means to detect and track glaucoma progression. Spectral-domain OCT has been demonstrated to measure the thickness of the ganglion cell and inner plexiform layers combined. (See, Loduca et al. “Thickness mapping of retinal layers by spectral-domain optical coherence tomography” Am J Ophthalmol 2010; 150(6): 849-855; or Wang et al. “Measurement of local retinal ganglion cell layer thickness in patients with glaucoma using frequency-domain optical coherence tomography” Arch Ophthalmol 2009; 127(7):875-881.)
Comparison of measurements to normative data is a common procedure for analyzing the health of a patient's eye. The anatomy of the ONH has considerable interindividual variability; it varies in size and shape, in the degree of tilt relative to the back of the eye and in the configuration of the large blood vessels that run through its center. These variations prevent accurate characterization of the ONH in a simple form that can be compared across individuals. The anatomy of the RNFL also has considerable interindividual variability. Bundles of ganglion cell axons, although they converge toward the ONH in a more-or-less radial pattern, do so along various paths, some more arcuate, some less, and sometimes with inferior or superior bifurcations. Thus the so-called TSNIT pattern (circular profile) of the peripapillary RNFL can be double or triple humped, with varying separation between the maxima. These variations decrease the diagnostic accuracy of comparisons to normative data in these regions (see for example U.S. Pat. No. 7,798,647 hereby incorporated by reference).
In contrast to the ONH and RNFL, the topographical homogeneity of the normal macular GCL+IPL apparent in FIG. 2 permits a characterization of the GCL or GCL+IPL as a canonical form, that is, as a standard way of presenting these layers. Such a canonical form can be regarded as a Standard Macula. FIG. 2 suggests that for the GCL or GCL+IPL, the Standard Macula has approximately the shape of a thickened elliptical annulus. Thus, although the GCL or GCL+IPL of normal maculas may vary in size, shape and thickness, all can be described by properties of a Standard Macula following suitable spatial transformation. Similarly, transformations applied to a Standard Macula permit comparison to the GCL or GCL+IPL of a patient's eye as a means of diagnosis.
Based on the above discussion, it is an object of the present invention to develop a method to characterize the thickness of layers of the macula in an effort to best discriminate normal from glaucomatous eyes and detect changes due to glaucoma over time. It is a further object of the invention to develop a means to compare this characterization to normative data with a reduced variance due to anatomical variations.